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Early this morning, the New England Journal of Medicine (NEJM) published the team paper "Total knee replacement after hemophilia B gene therapy" by Professor Zhang Lei, vice president of the Hematology Hospital (Institute of Hematology) of the Chinese Academy of Medical Sciences and deputy director of the State Key Laboratory of Experimental Hematology, reporting a case
of hemophilia patient who successfully underwent right total knee replacement after gene therapy.
The patient with severe hemophilia B had received coagulation factor IX.
-Padua gene therapy, underwent knee replacement for the next 16 months, did not receive any exogenous coagulation factor IX preparation replacement therapy during the perioperative period, did not suffer a large amount of blood loss, and reached a normal hemostatic level
.
This case suggests that in vivo FIX.
Padua has a good hemostatic effect
after gene therapy.
Zhang Lei is the corresponding author of the paper, and his colleague Xue Feng, chief physician and doctoral student Wang Panjing, and chief physician Yuan Zhen of Shandong Qianfoshan Hospital are the co-first authors
.
When hemophilia arthropathy progresses to the end, it usually requires total joint replacement, which is a major surgery
that requires high hemostatic ability.
Gene therapy technology using adeno-associated virus (AAV) carrying the highly active mutant coagulation factor IX.
Padua (Arg338Leu) encoding fragment as the vector has been successful in many clinical trials of hemophilia B gene therapy, but the hemostatic effect of coagulation factor IX.
Padua produced by gene therapy has not been confirmed
in vivo in clinical scenarios with high hemostatic ability.
We report here a patient with hemophilia B who underwent unilateral total knee replacement after AAV vector (BBM-H901)-mediated gene therapy carrying the clotting factor IX.
-Padua gene and did not receive exogenous factor IX replacement therapy
perioperatively.
The 26-year-old patient with severe hemophilia B received coagulation factor IX.
-Padua gene therapy and had no vector-related adverse events
during the 52-week follow-up period.
The one-phase detection of coagulation factor IX.
activity (FIX.
:C) based on activated partial thromboplastin time (APTT) (APTT reagent: Dade Actin FSL, automatic hemagglutinator: Siemens Sysmex CS-5100 system) showed that the FIX.
:C level in vivo of the patient after gene therapy was 51.
4~85.
0 IU/dL (Figure 1A).
Although the patient had no bleeding events after gene therapy and did not need to be transfused with coagulation factor IX, his hemophilia arthropathy, especially the right knee joint, still deteriorated, and his Hemophilia Early Arthropathy Detection with Ultrasound in China, HEAD-US-C) score (range: 0~78 points, Higher scores indicate poorer joint health) increased from 35 points at baseline to 43 points
at 1 year follow-up.
The imaging results and range of motion of the right knee are shown in Figures 2 and 3
.
Figure 1.
Patients with hemophilia B who underwent total knee replacement after gene therapy
Figure A shows the preoperative coagulation factor IX.
activity level
after transfusion of the coagulation factor IX.
-Padua gene carrier BBM-H901.
The dotted line shows an activity level of 40 IU/dL
.
The left panel of Figure B shows the activity level of coagulation factor IX measured using the Dade Actin FSL activated partial thromboplastin time (APTT) reagent, as measured by the first-phase method, and the perioperative coagulation factor IX inhibitor detection, and the right panel of Figure B shows the activity
of other coagulation factors (coagulation factors II, V.
, VII, VIII.
, X.
, XI.
, and XII).
The left panel of Figure C shows changes in prothrombin time and APTT after surgery, and the right panel of panel C shows changes in
fibrinogen and D-dimer levels.
Figure 2 MRI of the right knee before total knee replacement
Figure 3 Appearance and range of motion of both knees before total knee replacement
The patient successfully underwent a total right knee replacement on day 479 after carrier infusion and did not receive any exogenous factor IX replacement therapy
.
The patient had normal hemostasis, no tourniquet during surgery, no excessive bleeding in the surgical field, and an estimated intraoperative blood loss of 150 mL, similar to that of the general population undergoing surgery (Figure 4).
Postoperative x-rays are shown in Figure 5
.
Postoperative only physical measures are given to prevent thrombosis
.
Patients receive normal rehabilitation without the need for infusion of factor IX
preparations.
The patient's surgical wound healed well and no infection occurred (Figure 6).
Figure 4 Bleeding during total knee replacement
Figure 5.
X-rays of the right knee before and after total knee replacement
The appearance of the right knee 42 days after total knee replacement
FIX.
: C levels were 50.
1 IU/dL preoperatively on the day of surgery and decreased to 46.
0 IU/dL
on the same day after surgery.
Good hemostatic effect suggests that the activity of endogenous coagulation factor IX.
-Padua is related
to hemostatic function in vivo.
One day after surgery, FIX.
:C levels rose to 53.
8 IU/dL
.
Changes in the level of FIX.
:C in patients indicate that transduced hepatocytes have strong continuous secretion ability
.
1~5 days after surgery, the level of FIX.
:C showed an upward trend, and the peak reached 79.
3 IU/dL
.
The FIX.
:C level then gradually decreases to a stable level of about 60 IU/dL (Figure 1B).
The FIX.
:C level measured with another APTT reagent (Dade Actin) was 1.
58±0.
13 times
the average (±SD) of the Dade Actin FSL reagent.
Other coagulation factor activity decreases slightly initially postoperatively and then returns to baseline or is elevated (Figure 1B).
The same trend is observed for prothrombin time or APTT (Figure 1C).
We consider elevated fibrinogen and D-dimer levels to be part of the normal postoperative process (Figure 1C).
The Bethesda test did not detect inhibitors
of coagulation factor IX.
Overall, this case shows a good hemostatic effect of FIX.
Padua in vivo after gene therapy during major surgery that requires high hemostatic ability, which is related
to the FIX.
:C level measured by the first-phase method.
Our case also supports FIX.
:C (i.
e.
, the lower limit of FIX.
:C, which is generally recommended for major surgery) sufficient to achieve good hemostasis in
major surgery.
Of course, this is only an individual report, and the hemostatic effect of FIX.
Padua in vivo and its correlation with FIX.
:C levels need to be further studied
.
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.
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.
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.
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